An Emory study has discovered why teenager’s brains may be especially vulnerable to cocaine. Exposure to small amounts of cocaine in adolescence can disrupt brain development and impair the brain’s ability to change its own habits, the study suggests.

Guest post from Brendan O’Flaherty

The results were published in the April 1, 2017 issue of Biological Psychiatry, by researchers at Yerkes National Primate Research Center.

Drug seeking habits play a major role in drug addiction, says senior author Shannon Gourley, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center. The first author of the paper is former Emory graduate student Lauren DePoy, PhD.

When it comes to habits, cocaine is especially sneaky. Bad habits like drug use are already very difficult to change, but cocaine physically changes the brain, potentially weakening its ability to “override” bad habits. Although adults are susceptible to cocaine’s effects on habits, adolescent brains are especially vulnerable.

“Generally speaking, the younger you are exposed to cocaine in life, the more likely you are to have impaired decision making,” Gourley says.

Shannon Gourley, PhD, in lab

To understand why adolescent brains are especially vulnerable to cocaine, the researchers studied the effects of cocaine exposure on how the mice make decisions about food.

“I think it’s pretty amazing that we can actually talk to mice in a way that allows them to talk back,” Gourley says. “And then we can utilize a pretty tremendous biological toolkit to understand how the brain works.”

Researchers injected adolescent mice five times with either saline or cocaine. Both groups of animals then grew up without access to cocaine. Researchers then trained the mice to press two buttons, both of which caused food to drop into the cage. Since both buttons rewarded the mice equally, the mice pushed each button half the time.

Over time, pushing the two buttons equally could become a habit. To test this, the researchers then played a trick on the mice. When one of the buttons was exposed, the researchers starting giving the mice food pellets for free, instead of rewarding them for button-pressing.

“What the mouse should be learning is: ‘Ah hah, wait a minute, when I have access to this button I shouldn’t respond, because my responding doesn’t get me anything,‘” Gourley says. Read more

The placebo effect plays a big role in clinical trials for mood disorders such as depression. Emory psychiatrist Andy Miller hit upon something several years ago that could clear a path around the placebo effect.

A recent paper in Psychotherapy and Psychosomatics from Miller and psychiatry chair Mark Rapaport looks at clinical trials testing an anti-inflammatory drug against psoriasis, to see whether participants’ depressive symptoms improved. This sidesteps a situation where doctors’ main targets are the patients’ moods.

“These studies emphasize how difficult it is to interpret findings when these drugs are treating more than one problem,” Miller says. “Better to have a simpler study with just depression.”

Still, this line of research could clarify who could benefit from anti-inflammatory treatments and illuminate viable biomarkers and pathways. Two studies now underway at Emory specifically recruit patients with high levels of the inflammatory marker CRP, which Miller’s previous study showed was helpful in predicting response to infliximab.

The new paper results from a collaboration with Eli Lilly. Lilly’s ixekizumab (commercial name: Taltz) is an antibody against the cytokine IL-17A, used to treat moderate to severe psoriasis. Taltz was approved by the FDA in 2016, after clinical trials published in the New England Journal of Medicine. Read more

Low estrogen levels may make women more susceptible to the development of post-traumatic stress disorder (PTSD) at some points in their menstrual cycles or lifetimes, while high estrogen levels may be protective.

New research from Emory University School of Medicine and Harvard Medical School provides insight into how estrogen changes gene activity in the brain to achieve its protective effects.

The findings, published in Molecular Psychiatry, could inform the design of preventive treatments aimed at reducing the risk of PTSD after someone is traumatized.

The scientists examined blood samples from 278 women from the Grady Trauma Project, a study of low-income Atlanta residents with high levels of exposure to violence and abuse. They analyzed maps of DNA methylation, a modification to the shape of DNA that is usually a sign of genes that are turned off.

The group included adult women of child-bearing age, in which estrogen rises and falls with the menstrual cycle, and women that had gone through menopause and had much lower estrogen levels.

“We knew that estrogen affects the activity of many genes throughout the genome,” says Alicia Smith, PhD, associate professor and vice chair of research in the Department of Gynecology and Obstetrics at Emory University School of Medicine. “But if you look at the estrogen-modulated sites that are also associated with PTSD, just one pops out.”

That site is located in a gene called HDAC4, known to be critical for learning and memory in mice. Genetic variation in HDAC4 among the women was linked to a lower level of HDAC4 gene activity and differences in their ability to respond to and recover from fear, and also differences in “resting state” brain imaging. Women with the same variation also showed stronger connections in activation between the amygdala and the cingulate cortex, two regions of the brain involved in fear learning. Read more

Editorial note: Although the research team here is careful and confirms the findings in independent groups and in brain imaging and fear discrimination experiments, this is a preliminary result. More needs to be explored about how these genetic variants and others affect positive emotions.

“With relatively few studies on genetic underpinnings of positive emotions, we face the challenges of a nascent research area,” the authors write.

“Resilience is a multidimensional phenomenon, and we were looking at just one aspect of it,” says first author Aliza Wingo. She worked with Kerry Ressler , now at Harvard, and Tanja Jovanovic and other members of the Grady Trauma Project team.

“Positive affect” is what the team was measuring, through responses on questionnaires. And the questions are asking for the extent that respondents feel a particular positive emotion in general, rather than that day or that week. Read more

Emory researchers have identified molecular mechanisms that regulate motivation and persistence in mice. Their findings could have implications for intervention in conditions characterized by behavioral inflexibility, such as drug abuse and depression.

Scientists showedÂ that by manipulating a particular growth factor in one region of the brain, they couldÂ tune up or down a mouseâ€™s tendency to persist in seeking a reward. In humans, this region of the brain is located just behind the eyes and is called the medial orbitofrontal cortex or mOFC.

â€œWhen we make decisions, we often need to gauge the value of a reward before we can see it — for example, will lunch at a certain restaurant be better than lunch at another, or worth the cost,â€ says Shannon Gourley, PhD, assistant professor of pediatrics and psychiatry at Emory University School of Medicine. â€œWe think the mOFC is important for calculating value, particularly when we have to imagine the reward, as opposed to having it right in front of us.â€

Being able to appropriately determine the value of a perceived reward is critical in goal-directed decision making, a component of drug-seeking and addiction-related behaviors. While scientists already suspected that the medial orbitofrontal cortex was important for this type of learning and decision-making, the specific genes and growth factors were not as well-understood.

The researchers focused on brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons in the brain. BDNF is known to play key roles in long-term potentiation and neuronal remodeling, both important in learning and memory tasks. Variations in the human gene that encodes BDNF have been linked with several psychiatric disorders.

Emory psychiatrist Andrew Miller and his team have been developing a different approach over the last few years: studying symptoms of depression in people who are being treated for something else. This allows them to sidestep, at least partially, the cultural construct of depression, from William Styron to Peter Kramer to direct-to-consumer television ads.

Interferon alpha, a treatment used against hepatitis C virus infection and some forms of cancer, is a protein produced by the immune system that spurs inflammation. It also can induce symptoms of depression, such as fatigue and malaise. There are some slight differences with psychiatric depression, which Millerâ€™s team describes here (less guilt!), but they conclude that there is a â€œhigh degree of overlap.â€

Miller and his colleagues, including Jennifer Felger and Ebrahim Haroon, have documented how interferon-alpha-induced inflammation affects the brains of hepatitis C and cancer patients in several papers. That research, in turn, informs their more recent fruitfulinvestigations of inflammation in the context of major depression. More on that soon.

The focus on PTSD co-occurring with depression. As the authors note, several studies looking at traumatized individuals found PTSD and depression together more often than they were present separately. This was true of Atlanta inner city residents in the Grady Trauma Project, veterans and survivors of the 2001 World Trade Center attack.

DICER: the gene whose activity is turned down in blood samples from people with PTSD plus depression. Its name evokes one of the three Fates in Greek mythology, Atropos, who cuts the thread of life. DICER is at the center of a cellular network of regulation, because it is part of the machinery that generates regulatory micro-RNAs.

The findings recapitulate work in mouse models of stress and its effects on the brain, with a connection to the many-tentacled Wnt signaling/adhesion protein beta-catenin.

Some past posts on the Grady Trauma Projectâ€™s scientific fruits follow. Read more

About one third of people with depression have high levels of inflammation markers in their blood. New research indicates that persistent inflammation affects the brain in ways that are connected with stubborn symptoms of depression, such as anhedonia, the inability to experience pleasure.

The findings bolster the case that the high-inflammation form of depression is distinct, and are guiding researchersâ€™ plans to test treatments tailored for it.

Anhedonia is a core symptom of depression that is particularly difficult to treat, says lead author Jennifer Felger, PhD, assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine and Winship Cancer Institute.

“Some patients taking antidepressants continue to suffer from anhedonia,” Felger says. “Our data suggest that by blocking inflammation or its effects on the brain, we may be able to reverse anhedonia and help depressed individuals who fail to respond to antidepressants.”

In a study of 48 patients with depression, high levels of the inflammatory marker CRP (C-reactive protein) were linked with a “failure to communicate”, seen through brain imaging, between regions of the brain important for motivation and reward.

Emory researchers have found that high inflammation in depression is linked to a “failure to communicate” between two parts of the brain: the ventral striatum (VS, vertical cross section) and the ventromedial prefrontal cortex (vmPFC, horizontal). Images from Felger et al, Molecular Psychiatry (2015).

Neuroscientists can infer that two regions of the brain talk to each other by watching whether they light up in magnetic resonance imaging at the same times or in the same patterns, even when someone is not doing anything in particular. They describe this as “functional connectivity.”

Now other scientistsÂ haveÂ substantiatedÂ a proposal that micro RNA in playing a role in sperm. See this story (“Sperm RNAs transmit stress”) from Kate Yandell in The ScientistÂ or this one from Rachel Zamzow at Spectrum, the Simons Foundation’s autism news site, for more. An added wrinkle is that thisÂ research showsÂ that descendantsÂ of stress-exposed mice show a muted response to stress.

The short summary is: researchers at Yerkes National Primate Research Center found that when a mouse learns to become afraid of a certain odor, his or her pups will be more Gafas Ray Ban Baratas sensitive to that odor, even though the pups have never encountered it.Â Both the parent mouse and pups have more space in the smell-processing part of their brains, called the olfactory bulb, devoted to the odor to which they are sensitive.

[Note: a feature on a similar phenomenon, transgenerational inheritance of the effects of chemical exposure, appeared in Science this week]

Somehow information about the parent’s experiences is being inherited. But how? Brian Dias and Kerry Ressler are now pursuing followup experiments to firmly establish what’s going on. They discuss their research in this video: